This study used functional magnetic resonance imaging (fMRI) to examine the association between brain activation during exposure to cocaine-related cues and relapse to drug use in cocaine-dependent (CD) patients. We imaged 17 CD subjects during a 2-week in-patient stay. The subjects then entered a 10-week outpatient placebo-controlled, double-blind randomized clinical trial where urine toxicologies were assessed three times weekly to calculate the treatment effectiveness score (TES). Worse TES correlated with BOLD activation in the left precentral, superior temporal, and posterior cingulate cortices (PCC), and right middle temporal and lingual cortices (R>0.65; P<0.005). The left PCC activation also distinguished eight nonrelapsers (TES above mean and completed treatment) from nine relapsers. Cocaine-free urines were significantly greater in the nonrelapsers (92%) than in the relapsers (66%), who also remained in treatment for an average of only 3.2 weeks. Self-reports of craving during fMRI did not differ between nonrelapsers and relapsers and did not correlate with TES. Relapse to cocaine abuse was associated with increased activation in the sensory association cortex, the motor cortex, and PCC while viewing images of cocaine-related cues. These results suggest that relapse to cocaine abuse is associated with increased brain activation to cocaine cues in sensory, motor, and cognitive-emotional processing areas. This physiological activation was a better predictor of relapse than subjective reports of craving, and may be a useful target for treatment development.